Methods for the dietary management of irritable bowel syndrome and carbohydrate malabsorption

ABSTRACT

The invention relates generally to digestive disorders, and in particular to methods for treating irritable bowel syndrome by increasing carbohydrate absorption by administering a composition containing a  Bacillus coagulans  bacterium.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 09/369,016filed Aug. 5, 1999, which claims the benefit of U.S. Ser. No.60/095,786, filed Aug. 7, 1998. This application also claims priority toU.S. Ser. No. 60/528,074, filed Dec. 5, 2003. Each application fromwhich is present present application claims priority is incorporatedherein by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to the utilization of probiotic lacticacid-producing bacteria in a nutritional composition. More specifically,the present invention relates to the use of Bacillus coagulans forincreasing the absorption of carbohydrates within the gastrointestinaltract of a mammal.

BACKGROUND OF THE INVENTION

The human digestive system uses a series of enzymes to break downcomplex foods into simple molecules (e.g., sugars, peptides and lipids)that can be absorbed by the body. The inability or diminished capacityof the body's production of one or more enzymes that are crucial forproper digestion can lead to gastrointestinal symptoms that have beencharacterized by the medical community as irritable bowel syndrome(IBS). A patient with IBS typically presents clinically with one ofthree variants: i) chronic abdominal pain and constipation (also knownas spastic colitis); ii) chronic intermittent diarrhea, often withoutpain; or iii) both features, in an alternating cycle of constipation anddiarrhea.

SUMMARY OF THE INVENTION

The invention is based, in part, on the discovery of the therapeuticeffects of Bacillus coagulans, a spore-forming lactic acid bacterium, inthe prevention and treatment of IBS and carbohydrate malabsorption.Carbohydrate malabsorption includes the inability of a mammal to fullydigest the naturally occurring sugars (e.g., lactose, fructose, andglucose) in foods and beverages.

In one aspect, the invention provides a method of reducing one or moresymptoms of irritable bowel syndrome, by identifying a patient sufferingfrom or at risk of developing irritable bowel syndrome, andadministering to the patient a composition that includes Bacilluscoagulans bacteria. Bacterial species include Bacillus coagulans, e.g.,Bacillus coagulans hammer, preferably Bacillus coagulans hammer strainAccession No. ATCC 31284, or strains derived from Bacillus coagulanshammer strain Accession No. ATCC 31284, such as, GBI-20 (ATCCDesignation Number PTA-6085); GBI-30 (ATCC Designation Number PTA-6086);and GBI-40 (ATCC Designation Number PTA-6087). (See, copending U.S.patent application Ser. No. 09/708,870, the contents of which areincorporated by reference in their entirety). Symptoms of IBS includediarrhea, constipation, alternating diarrhea and constipation, gas,bloating, urgency, and abdominal pain (intestinal discomfort). Thecomposition also includes a supplementary enzyme (e.g., a lactase, afructase, a lipase, or a protease), an anti-diarrheal agent (e.g.,loperamide, attapulgite, Croton Lechleri Extract, or calciumpolycarbophil), an anti-gas agent (e.g., α-galactosidase enzyme,simethicone, calcium carbonate, aluminum hydroxide or magnesiumhydroxide), or a laxative (e.g., a senoside such as senosides A, B, C orD, docusate sodium, magnesium hydroxide, or a dietary fiber). Asupplemental lactase includes an enzyme that catalyzes the hydrolysis oflactose in the gastrointestinal tract of a mammal, in a concentrationthat exceeds the amount of lactase that is present in the small or largeintestine of a mammal prior to Bacillus coagulans colonization. Thecomposition contains an isolated lactose, i.e., an enzyme that has beenpurified from a cell which produces the enzyme. A supplemental fructaseincludes an enzyme that catalyzes the hydrolysis of fructose in thegastrointestinal tract of a mammal, in a concentration that exceeds theamount of fructase that is present in the small or large intestines of amammal prior to Bacillus coagulans colonization. The gastrointestinaltract is the system of organs in a mammal including the mouth (buccalcavity), pharynx, esophagus and cardia, stomach(s), and intestines.

Colonization of Bacillus coagulans bacteria generally occurs between24-48 hours following delivery. Continued colonization is improved bythe repeated administration of Bacillus coagulans, such as dailyadministration. Generally, the supplementary fructase is provided at adose of from about 1000 IU to about 12,000 IU, and the supplementarylactase is provided at a dose of from about 1000 IU to about 12,000 IU.In some treatment regimens, the target patient pool is female, such as afemale that is post-menstrual or post-menopausal. Alternatively, thepatient is male.

A therapeutic does includes Bacillus coagulans bacteria at aconcentration of from about 1×10⁴ to about 1×10¹² viable bacteria,specifically about 1×10⁶ to about 1×10¹¹, more specifically about 1×10⁸to about 1×10¹⁰, and most specifically about 8×10⁸. The Bacilluscoagulans bacteria are in the form of spores, vegetative cells, or acombination thereof.

The invention also provides a method of reducing one or more symptoms ofirritable bowel syndrome, by identifying a patient suffering from or atrisk of developing irritable bowel syndrome, and administering to thepatient a composition including an effective IBS inhibiting amount ofBacillus coagulans bacteria prior to or concomitant with the onset ofone or more IBS symptoms. Symptoms of IBS include diarrhea,constipation, alternating diarrhea and constipation, bloating, urgency,and abdominal pain.

In another aspect, the invention, the invention provides a method ofreducing a symptom of irritable bowel syndrome, by identifying a patientsuffering from or at risk of developing irritable bowel syndrome, andadministering to the patient a composition that includes a supplementaryenzyme, preferably a fructase and a lactase.

The invention also provides a method of diagnosing irritable bowelsyndrome in a patient, including the steps of identifying a patienthaving a symptom of irritable bowel syndrome, providing apatient-derived biological sample from the identified patient,determining an amount of a product of a gastrointestinal enzyme in thepatient-derived sample, and comparing the amount in the patient-derivedsample with a reference amount of a product of a gastrointestinalenzyme, whereby an alteration in the test amount relative to thereference amount indicates that the patient has irritable bowelsyndrome.

A gastrointestinal enzyme includes any enzyme that is active in thegastrointestinal tract, particularly the stomach and the small and largeintestines. A biological sample includes any solid, liquid, or gaseousmaterial obtained from a mammal, such as a human patient. The symptomsof IBS include diarrhea, constipation, or alternating diarrhea andconstipation. The gastrointestinal enzyme includes a lactase, afructase, a lipase and a protease. In embodiments of the invention, thepatient identified as having a symptom of irritable bowel syndrome hasone or more symptoms classified under the Rome Criteria. The amount ofthe product of a gastrointestinal enzyme in the patient-derived sampleis modulated following administration of the compositions of theinvention. For example, hydrogen measured using the hydrogen breath testdeclines following administration of a Bacillus coagulans-containingcomposition.

In another aspect, the invention provides a method of improving stoolconsistency in a patient afflicted with non-constipated IBS, byadministering an effective amount of a Bacillus coagulans bacteriaprovided at a concentration of from about 1×10⁸ to about 1×10¹⁰ viablebacteria, where the patient's stool consistency is improved followingthe administration. For example, abnormal patient stool is characterizedas lumpy/hard or loose/watery and an improvement includes lessconstipated or diarrhea stool.

In a further aspect, the invention relates to a method of decreasingurgency in a subject afflicted with IBS, by administering an effectiveamount of a Bacillus coagulans bacteria provided at a concentration offrom about 1×10⁸ to about 1×10¹⁰ viable bacteria wherein urgency isdecreased following the administration. Incontinence of stool is aninability to control or delay bowel movements until an appropriate time,e.g., until one can get to a toilet. Urgency is a sudden urge to have abowel movement that is so strong that if a toilet is not immediatelyavailable, incontinence will occur.

The invention also provides a composition that includes a Bacilluscoagulans bacteria, a supplementary lactase (e.g., β-galactosidase), anda supplementary fructase. Generally, the supplementary lactase isprovided in a concentration from about 1000 IU to about 12,000 IU (e.g.,about 3000 IU), and the supplementary fructase is provided in aconcentration from about 1000 IU to about 12,000 RU (e.g., about 3000IU). The composition also includes an anti-diarrheal agent, an anti-gasagent, a laxative, a vitamin, a mineral, an isolated amino acid, asource of dietary fiber, or an antibiotic. The composition may alsoinclude a pharmaceutically-acceptable carrier containing, e.g.,silicone. The composition is in the form of a capsule, tablet (includinga chewable tablet), powder, liquid or in a formulation with a foodproduct. Food products include dairy products including ice cream,nutritional bars (energy or candy bars), sugar substitutes, non-dairycreamers, tea bags, and similar products. Sources of dietary fiberinclude psyllium husk, soy fiber, citrus fiber, beet fiber, pumpkin seedmeal, ground flax, black walnut hull, rice fiber, hydrocollodialpolysaccharides, pecan husks, and peanut husks.

The invention provides a composition containing a Bacillus coagulansbacteria and a supplemental enzyme provided in a formulation with a foodproduct. For example, the food product is a dairy product (a productcontaining a component obtained from the milk of a cow, sheep, goat, orsimilar mammal).

The invention further provides a composition that includes from about1×10⁸ to about 1×10¹⁰ Bacillus coagulans bacteria, a supplementallactase in a concentration of about 3000 IU, a supplemental fructase ina concentration of about 3000 IU, and manganese stearate.

The invention also provides a composition that includes an isolatedlactase provided in a concentration from about 1000 IU to about 12,000IU per dose and an isolated fructase provided in a concentration fromabout 1000 IU to about 12,000 IU per dose. The composition also includesan anti-diarrheal agent, an anti-gas agent, a laxative, a vitamin, amineral, an isolated amino acid, a source of dietary fiber, anantibiotic, or a combination thereof.

The invention also provides a method for increasing carbohydrateabsorption in a mammal, by administering to a mammal a composition thatincludes a Bacillus coagulans bacteria, a supplementary lactase (e.g.,provided in a concentration from about 1000 IU to about 12,000 IU), anda supplementary fructase (e.g., provided in a concentration from about1000 IU to about 12,000 IU), where carbohydrate absorption is increasedfollowing the administration. The mammal is diagnosed as suffering fromor being at risk of developing a disorder associated with carbohydratemalabsorption. Disorders associated with carbohydrate malabsorptioninclude lactose intolerance, fructose intolerance, glucose-galactoseintolerance, sorbitol intolerance, irritable bowel syndrome, short bowelsyndrome, stagnant loop syndrome, celiac disease, chronic malnutrition,chronic persistent diarrhea, immunoproliferative small intestinaldisease, intractable diarrhea of infancy, postenteritis syndrome,tropical sprue, Whipple's disease, Wolman disease, Crohn's disease andulcerative colitis. The composition optionally includes ananti-diarrheal agent, an anti-gas agent, a laxative, a vitamin, amineral, an isolated amino acid, a source of dietary fiber, or anantibiotic.

The invention further provides a method for increasing lactosedigestion, including the steps of identifying a patient suffering fromor at risk of developing lactose intolerance, and administering to thepatient a composition that includes Bacillus coagulans bacteria and asupplemental lactase (e.g., provided in a concentration from about 1000IU to about 12,000 IU), whereby lactose digestion is increased followingthe administration.

The invention also provides a composition including a Bacillus coagulansbacteria and a supplementary fructase, e.g., a fructase provided in aconcentration from about 1000 IU to about 12,000 IU. The compositionalso includes an isolated amino acid. The composition is provided in theform of a capsule, tablet (including chewable tablet), powder, liquid orin a formulation with a food product. The Bacillus coagulans bacteriaare derived from Bacillus coagulans Hammer strain Accession No. ATCC31284.

In another aspect, the invention provides a medical food for themanagement of irritable bowel syndrome, that includes Bacillus coagulansbacteria and an isolated amino acid (e.g., L-lysine), wherein saidmedical food is formulated to provide at least about 1×10⁶ (e.g., 1×10⁷,1×10⁸ or 8×10⁸ or more) viable Bacillus coagulans bacteria in thegastrointestinal tract of a mammal per day based on a serving size ofabout 0.5 gram to about 25 grams of the medical food taken up to twice aday. In embodiments of the invention, the medical food is provided at adosage such that colonization of about 1×10⁵ (e.g., 1×10⁶ or 1×10⁷)viable Bacillus coagulans bacteria per gram of fecal material in amammal following consumption of the medical food. In embodiments of theinvention, the medical food includes a supplemental enzyme such as alactase, a fructase, a lipase or a protease. In other embodiments, themedical food includes an anti-diarrheal agent, an anti-gas agent, alaxative, a vitamin, a mineral, an appropriate amino acid(s), a sourceof dietary fiber, and/or an antibiotic.

In a further aspect, the invention provides a method of dietarymanagement of a subject's carbohydrate absorption, including the stepsof identifying a patient having a symptom of carbohydrate malabsorption,and providing a composition comprising Bacillus coagulans bacteria tothe identified patient, wherein the bacteria colonize the subject'sgastrointestinal tract, whereby carbohydrate absorption by the subjectis modulated, such that the subject's carbohydrate absorption and ismanaged. The dietary management of the subject's carbohydrate absorptionresults in a reduction or elimination of one or more of the symptoms ofcarbohydrate malabsorption.

In another aspect, the invention provides a method of dietary managementof a subject's carbohydrate absorption, including the steps ofidentifying a patient having a symptom of carbohydrate malabsorption,providing a patient-derived biological sample from the identifiedpatient, determining an amount of a product of a gastrointestinal enzymein the patient-derived sample, comparing the amount in thepatient-derived sample with a reference amount of a product of agastrointestinal enzyme, and providing a composition comprising Bacilluscoagulans bacteria, whereby the subject's carbohydrate absorption ismanaged. The amount of a product of a gastrointestinal enzyme in thepatient-derived sample is determined using hydrogen and/or methanebreath testing. The amount of the product in the patient-derived sampledeclines following administration of the Bacillus coagulans-containingcomposition. The patient's carbohydrate absorption is managed such thatone or more symptoms of carbohydrate malabsorption are decreased oreliminated.

The invention further provides a method for increasing carbohydrateabsorption in a patient diagnosed as suffering from or being at risk ofdeveloping celiac disease, by administering to the subject a compositioncomprising Bacillus coagulans bacteria, wherein carbohydrate absorptionin the patient is increased following the administration.

In another aspect, the invention provides a method of reducing a symptomof IBS, wherein the symptom includes alternating diarrhea andconstipation, by identifying a patient suffering from or at risk ofdeveloping irritable bowel syndrome, and administering to the patient acomposition including Bacillus coagulans bacteria in dose that reducesone or more symptoms of IBS.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In the case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION

Medical diagnosis of IBS was based on the absence or presence of anumber of symptoms, which are generally regarded as typical of IBS andare provided, for example, by the “Rome Criteria” (See, W. G. Thompsonet al., Gastroent. Int. 2 (1989) 92-95; W. G. Thompson et al., Gut 45/11(1999) 1143-II 47; W. G. Thompson, Lancet 341 (1993) 1569-1572), and theRome II Criteria. Guidelines for IBS diagnosis under the Rome criteriainclude the continuous or recurrent symptoms of abdominal pain ordiscomfort that may be relieved with defecation, may be associated witha change in frequency, or may be associated with a change in theconsistency of stools; and that two or more of the following symptomsare present at least 25 percent of the time: altered stool frequency(greater than 3 bowel movement per day or less than 3 bowel movementsper week), altered stool form (hard or loose watery stools or poorlyformed stools), passage of mucous stools, and bloating (feeling ofabdominal distention).

The Rome II Diagnostic Criteria (a system for diagnosing functionalgastrointestinal disorders based on symptoms) for IBS is as follows:

At least 12 weeks or more, which need not be consecutive, in thepreceding 12 months of abdominal discomfort or pain that is accompaniedby at least two of the following features:

-   -   1) It is relieved with defecation, and/or    -   2) Onset is associated with a change in frequency of stool,        and/or    -   3) Onset is associated with a change in form (appearance) of        stool.

Other symptoms that are not essential but support the diagnosis of IBS:

Abnormal stool frequency (greater than 3 bowel movements/day or lessthan 3 bowel movements/week); Abnormal stool form (lumpy/hard orloose/watery stool); Abnormal stool passage (straining, urgency, orfeeling of incomplete evacuation); Passage of mucus; Bloating or feelingof abdominal distension.

The importance of carbohydrates in the onset of IBS symptoms hasrecently been discussed. (See, Scand J Gastroenterol. 1998.33(11):1158-63, Isr Med Assoc J. 2000. 2(8):583-7, Am J Gastroenterol.2003. 98(6):1348-53). IBS and carbohydrate malabsorption have often beenconfused for one another. Reliable diagnosis is critical to determiningthe appropriate dosage for treating the symptoms of IBS. The presentinvention provides diagnostic methods for the detection and diagnosis ofIBS in patients, such as humans, who are suffering from IBS, or are atrisk of developing IBS.

The present invention also provides methods for the reduction ofsymptoms of IBS. Prior to the present invention, it has been difficultto effectively reduce symptoms in the treatment of irritable bowelsyndrome. The goals of therapeutic treatment were to reduce the varietyof complaints, and to improve conditions so as to decrease morbidity andincrease the quality of the patient's daily life. Therapeutic treatmentsinclude psychotherapy, life guidance, diet therapy, and drug therapyused on a symptomatic basis against the patient's complaints. Compoundsincluding opioid agonists (e.g., loperamide) or anticholinergic agents(e.g., mepenzolate bromide and timepidium bromide) have been used tocontrol hypermotility of the digestive tract, and benzodiazepine drugs(e.g., diazepam) have been prescribed for anxiety, insomnia and similarcomplaints. Recently, antagonists of 5-hydroxytryptamine (5-HT;serotonin) and 5-HT receptors have been used to treat IBS. (See, U.S.Pat. No. 6,429,209). A deficiency of these treatments is that they areusually incapable of reducing or eliminating multiple symptoms of IBS,particularly when the patient presents with alternations of diarrhea andconstipation. The compositions of the present invention alleviatemultiple symptoms of carbohydrate malabsorption, including pain, flatus,abdominal bloating, diarrhea, constipation, and alternating diarrhea andconstipation.

The present invention also provides methods of treatment of diseasesassociated with carbohydrate malabsorption. These diseases, in additionto IBS, include lactose intolerance, fructose intolerance,glucose-galactose intolerance, sorbitol intolerance, short bowelsyndrome, stagnant loop syndrome, celiac disease, chronic malnutrition,chronic persistent diarrhea, immunoproliferative small intestinaldisease, intractable diarrhea of infancy, postenteritis syndrome,tropical sprue, Whipple's disease, Wolman disease, Crohn's disease andulcerative colitis.

Bacillus coagulans

Bacillus coagulans is a strain of bacteria that possesses the ability tosporulate, making the strain resistant to heat and other conditions, aswell as providing for a long shelf-life in product formulations.Further, Bacillus coagulans is ideal for survival and colonization oftissues under conditions of pH, salinity, and the like within thegastrointestinal tract. Additionally, Bacillus coagulans isnon-pathogenic. Preferred methods disclosed herein utilize Bacilluscoagulans cells and spores. Methods of preparing Bacillus coagulansvegetative cells and spores are presented in Example 1.

Bacillus coagulans bacteria colonize the gastrointestinal tract of amammal to which they are provided enterically. Generally, colonizationoccurs within twenty four to forty eight hours following administration.Efficiency of intestinal colonization of a mammal is determined, e.g.,by quantitating the number of Bacillus coagulans bacteria per gram ofthe mammal's feces. A mammal has been colonized by the Bacilluscoagulans bacteria of the present invention if the mammal's fecescontain greater than 1×10⁴ viable bacteria per gram of feces, preferably1×10⁵ viable bacteria per gram of feces. Preferably, the feces contain1×10⁶ viable bacteria per gram of feces.

One species of Bacillus coagulans, that is useful in this invention, hadpreviously been mischaracterized as a Lactobacillus; this bacterium waslabeled as Lactobacillus sporogenes. However, initial classification wasincorrect due to the fact that Bacillus coagulans produces spores andthrough metabolism excretes L(+)-lactic acid, both aspects which providekey features to its utility. Instead, these developmental and metabolicaspects required that the bacterium be classified as a lactic acidBacillus, and therefore it was re-designated. Accordingly, the bacteriauseful in the invention (i) possess the ability to produce and excreteenzymes useful in digestion (e.g., lactase, various proteases, lipasesand amylases); (ii) demonstrate beneficial function within thegastrointestinal tract; and (iii) are non-pathogenic.

The Gram positive rods of Bacillus coagulans have a cell diameter ofgreater than 1.0 μm with variable swelling of the sporangium, withoutparasporal crystal production. Bacillus coagulans is a non-pathogenic,Gram positive, spore-forming bacteria that produces L(+) lactic acid(dextrorotatory) under homo-fermentation conditions. It has beenisolated from natural sources, such as heat-treated soil samplesinoculated into nutrient medium (see e.g., Bergey's Manual of SystemicBacteriology, Vol. 2, Sneath, P. H. A. et al., eds., Williams & Wilkins,Baltimore, Md., 1986). Purified Bacillus coagulans strains have servedas a source of enzymes including endonucleases (e.g., U.S. Pat. No.5,200,336); amylase (U.S. Pat. No. 4,980,180); lactase (U.S. Pat. No.4,323,651) and cyclo-malto-dextrin glucano-transferase (U.S. Pat. No.5,102,800). In particular, Bacillus coagulans strains have been used asgeneral nutritional supplements and agents to control constipation anddiarrhea in humans and animals.

Various Bacillus coagulans bacterial strains which are currentlycommercially available from the American Type Culture Collection (ATCC,Manassas, Va.) include the following accession numbers: Bacilluscoagulans Hammer NRS 727 (ATCC No. 11014); Bacillus coagulans Hammerstrain C (ATCC No. 11369); Bacillus coagulans Hammer (ATCC No. 31284);and Bacillus coagulans Hammer NCA 4259 (ATCC No. 15949). PurifiedBacillus coagulans bacteria are also available from the DeutscheSarumlung von Mikroorganismen und Zellkuturen GmbH (Braunschweig,Germany) using the following accession numbers: Bacillus coagulansHammer 1915 (DSM No. 2356); Bacillus coagulans Hammer 1915 (DSM No.2383, corresponds to ATCC No. 11014); Bacillus coagulans Hammer (DSM No.2384, corresponds to ATCC No. 11369); and Bacillus coagulans Hammer (DSMNo. 2385, corresponds to ATCC No. 15949). Bacillus coagulans bacteriacan also be obtained from commercial suppliers such as K.K. Fermentation(Kyoto, Japan) and Nebraska Cultures (Walnut Creek, Calif.).Compositions include strains or variants derived from Bacillus coagulansHammer strain ATCC No. 31284 such as ATCC PTA-6085, PTA-6086, orPTA-6087.

Bacillus coagulans bacteria are provided in amounts sufficient tocolonize the gastrointestinal tract of a mammal. The invention providesBacillus coagulans bacteria at a concentration of from about 1×10⁴ toabout 1×10¹² viable bacteria, specifically about 1×10⁶ to about 1×10¹¹,more specifically about 1×10⁸ to about 1×10¹⁰, and most specificallyabout 810⁸ . Bacillus coagulans bacteria are provided as vegetativecells, spores, or a combination thereof.

Fructase

The fructase of the invention is an enzyme that catalyzes the hydrolysisof fructose in the gastrointestinal tract of a mammal. Fructase ispurified from a fungus such as Aspergillus oryzae. Fructase is alsocommercially available from Specialty Enzymes and Biochemicals (Chino,Calif.), Spectrum Chemicals (Los Angeles, Calif.), and Solvay Enzymes(Edison, N.J.).

Fructase activity is measured in vivo using the hydrogen ion breathtest. A patient who has abstained from carbohydrates for at least twelvehours is given a 33% fructase solution (50 g per 150 ml of water), andend-expiratory breath samples are collected before (the baseline value)and every 15-30 minutes for four to six hours after sugar ingestion.Hydrogen (and other gases such as methane) breath concentrations aremeasured using gas chromatography. A person is defined as fructoseintolerant if a rise of at least 3 parts per million (ppm) over threeconsecutive breath tests from the baseline value or a value over 20 ppmfollowing sugar ingestion is observed.

Lactase

The lactase of the invention is an enzyme that catalyzes the hydrolysisof lactose in the stomach and/or intestine. In certain embodiments, twolactases with different optimum pH ranges are used (e.g., a firstlactase that has an optimum pH range that encompasses pH 3.0 to about pH6.0, and a second lactase that preferably has an optimum pH range thatencompasses about pH 6.0 to about pH 8.0). An optimum pH range means thepH over which the hydrolytic activity of the lactase is within about 10to 100 percent of its maximum, and optimum pH value means the pH atwhich the lactase exhibits maximum hydrolytic activity.

Lactases derived from fungi are generally known to have optimum pHvalues which fall within the acid range. Genera of fungi useful inobtaining lactases include Aspergillus; Mucor; Fusarium; Scopuloriopsis;Alternaria; and Curvularia and the bacterium Thermus aquaticus. Thelactases, having the optimum pH value shown in the parentheses, arepreferably derived from the following fungi: Aspergillus oryzae;(4.5-5.0) Aspergillus niger (3.0-4.0); Fusarium moniliforme (3.8-5.0);Scopulariopsis (3.6-5.0); Mucor pucillus (4.5-6), Alternaria alternara(4.5-5.3); and Curvularia inaegualis (3.4-4.3) and the bacterium Thermusaquaticus (4.5-5.5).

Lactases derived from yeast and bacteria are generally known to haveoptimum pH values in the more neutral region, including Kluyveromyces(Saccharomyces), Lactobacillus, Bacillus, Streptococcus, andEscherichia. Lactase derived from the following organisms, having theoptimum pH value shown in the parentheses, are preferred: Kluyveromyceslactis (6.5), Kluyveromyces fragilis (6.6), Lactobacillus thermophilus(6.2-7.1), Bacillus circulans (6.0), Lactobacillus bulgaricus (7.0),Leuconostoc citrovorum (56.5), Bacillus stearothermophilus (6.0-6.4),Streptococcus thermophilus (6.5-7.5), and Bacillus sp. (6.8).

The lactases used in the present invention are produced by a variety ofwell known techniques. Many of these lactases are produced by commercialprocesses which cultivate the bacterium, yeast or fungus, and thenisolate the lactase from the culture or culture broth of themicroorganism. Further techniques for preparing such lactases may befound in U.S. Pat. No. 3,629,073; U.S. Pat. No. 3,718,739; and U.S. Pat.No. 3,919,049, all of which are hereby incorporated by reference.

Lactase activity is measured in vivo using the hydrogen ion breath test.A patient who has abstained from carbohydrates for at least twelve hoursis given a lactose solution (18-50 g), and end-expiratory breath samplesare collected before and every 15-30 minutes for four to six hours aftersugar ingestion. Hydrogen (and other gases such as methane) breathconcentrations are measured using gas chromatography. An increase inbreath hydrogen concentration of 10 parts per million (ppm) followingsugar ingestion is typically observed in non-lactose intolerantpatients. Incomplete absorption of carbohydrate is defined as anincrease in breath hydrogen of 20 ppm (or its equivalent of 5 ppm inmethane) following sugar ingestion.

Lactase activity is quantified in units. An FCC lactase unit (FCC LacU), and IU and a neutral lactase unit are defined as that quantity ofenzyme that will liberate 1 μmol of o-nitrophenol fromo-nitrophenyl-β-D-galactoside per minute under the conditions, of theassay described in Food Chemicals Codex, National Academy Press, Wash.,D.C., pp. 491-2 (1981), which is hereby incorporated by reference, at pH4.5 and 6.5, respectively.

Other Gastrointestinal Enzymes

Amylase (α-1,4-glucan 4-glucanohydrolase, EC 3.2.1.1.) activity isdetermined using the method of Somogyi (See, Somogyi, 1960.“Modification of two methods for the assay of amylase.” Clin Chem.6:23-35). One amylase activity unit is defined as the amount of amylasethat will cause the formation of reducing power equivalent to 1 mgglucose in 30 minutes at 40 degrees C. per milligram of intestinaldigesta protein. Cornstarch is an amylase substrate useful forcalibration of amylase activity units.

Lipase (e.g., lps aw 02513, triacylglycerol lipase, EC 3.1.1.3.)activity is assayed using the method of Tietz and Fiereck (See, Tietzand Fiereck, 1966. Clin. Chim. Acta 13:352-58). One lipase activity unitis equal to the volume (mL) of 0.05 M NaOH required to neutralize thefatty acid liberated during a 6 hour incubation with 3 mL of lipasesubstrate (e.g., olive oil) at 37 degrees C. per milligram of digestaprotein. Lipases can be purified from Bacillus subtilis and Pseudomonasaruginosa and are also commercially available.

Peptidases and proteases include enzymes that degrade a polypeptide byhydrolysis of the peptide bonds. Peptidases include amino-, dipeptidyl-,and tripeptidyl-peptidases. Useful proteases include Arg-C proteinase,Asp-N endopeptidase, caspases, chymotrypsin, clostripain, enterokinase,granzyme B, glutamyl endopeptidase, pepsin, proline-endopeptidase,proteinase K, Staphylococcal peptidase I, thermolysin, thrombin andtrypsin.

Composition Formulations

The compositions of the present invention are combined with apharmaceutically acceptable carrier and are preferably administeredorally. The unit dosages of these compositions may be in the form ofsolid preparations, such as tablets, pills, capsules, caplets, powders,granules and wafers, or liquid preparations, such as suspensions ordispersions in aqueous or non-aqueous vehicles, such as syrups andelixirs.

The compositions of the present invention optionally contain componentsin addition to the Bacillus coagulans bacteria. Additional componentsinclude supplementary enzymes, anti-diarrheal agents, anti-gas agents,laxatives, dietary fibers, isolated amino acids, vitamins, minerals,antibiotics, and buffering agents.

Supplementary enzymes include a lactase, a fructase, a lipase, and aprotease. Generally, a supplementary enzyme is provided in an amountexceeding the amount of the enzyme contained in or produced by theBacillus coagulans bacteria provided in the therapeutic composition. Forexample, a supplemental lactase is an amount of purified lactase that isadministered to digest the lactose present in the gastrointestinal tractof a mammal.

Anti-diarrheal agents include any compounds that reduce diarrhea, suchas by reducing water content in the stool. Preferred anti-diarrhealagents include loperamide (such as loperamide HCL), attapulgite, CrotonLechleri Extract, and calcium polycarbophil.

Anti-gas agents include compounds that reduce gas in thegastrointestinal tract of a mammal. Preferred anti-gas agents includeα-galactosidase enzyme, simethicone, calcium carbonate, aluminumhydroxide or magnesium hydroxide.

Laxatives include any compound that increases stool density or frequencyof bowel movements. Preferred laxatives include senosides, docusatesodium, magnesium hydroxide, and a dietary fiber. Senosides includehydroxyanthracene glycosides such as senosides A, B, C or D, generallyobtained from pulverized Cassia acustifolia husk. Exemplary dietaryfibers include psyllium husk, soy fiber, citrus fiber, beet fiber,pumpkin seed meal, ground flax, black walnut hull, rice fiber,hydrocollodial polysaccharides, pecan husks, and peanut husks.

Isolated amino acids include alanine, arginine, asparagine, asparticacid, cysteine, glutamic acid, glutamine, glycine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,threonine, tryptophan, tyrosine, and valine. Preferably, the isolatedamino acid is lysine.

The compositions are usable in the form of medicines, foods, and drinks,including supplements, medical foods, health foods, nutraceuticals, anddietary supplements, as directed by a healthcare practicioner. A medicalfood is prescribed by a physician when a patient has special nutrientneeds in order to manage a disease or health condition such as IBS orcarbohydrate malabsorption, and the patient is under the physician'songoing care.

In preparing solid unit dosage forms, the compositions of the presentinvention (e.g., Bacillus coagulans bacteria) are mixed withconventional solid fillers or carriers, such as silicone, starch, talc,calcium phosphate, calcium sulfate, calcium stearate, magnesiumstearate, stearic acid, sorbitol, mannitol, gelatin, natural orsynthetic gums, such as carboxymethylcellulose, methylcellulose,alginates, dextrans, acacia gum, karaya gum, locust bean gum, tragacanthand other conventional carriers. Additionally, other excipients such asdiluents, binders, lubricants, disintegrants, colors and flavoringagents may be employed.

Suitable liquid forms of the present invention can be prepared byincorporating the lactase in aqueous or non-aqueous dispersions,suspensions, or solutions. Conventional liquid carriers such asglycerol, and edible glycols, edible oils, such as cottonseed oil,soybean oil, corn oil, peanut oil, safflower oil, and other triglycerideoils, and dispersing or suspending agents, such as the aforementionednatural and synthetic gums.

Conventional methods are employed for preparing the solid and liquidforms of the present invention. Suitable techniques are described inRemington's Pharmaceutical Sciences, 18th Ed., Chapters 83 and 89(1990), which is hereby incorporated by reference.

The compositions are produced in powdered or granular form for directadmixture with food products consumed by subjects suffering from IBS orother carbohydrate malabsorption diseases. For instance, in the case ofa lactose intolerant infant, a suitable amount of the Bacillus coagulansand lactase-containing composition, in a powdered or granular form, isadded directly to the milk or other food consumed by the infant. In thecase of an animal, such as a mammal, that normally requires a dietaryregime of whey, the compositions of the present invention may be addeddirectly to the whey.

The composition optionally contains an enteric coating, such as coatingof a Bacillus coagulans bacterium as a vegetative cell. This coatingremains intact in the stomach, but dissolves and release the vegetativecell once it reaches the more neutral environment of the smallintestine. Suitable enteric coatings include amylose acetate phthalates,styrene-maleic acid copolymer, cellulose acetate succinate, celluloseacetate phthalate, polyvinyl acetate phthalate,hydroxy-propylmethylcellulose phthalate, fatty acids, fatty acid esters,glycerol esters, polyglycerol esters, paraffin waxes, camauba wax,formalized gelatin, shellac and hydrogenated vegetable waxes, such ashydrogenated castor oil and cottonseed oil. Other suitable entericcoatings are disclosed in Liebernan, H. A. et al., Pharmaceutical DosageForms: Tablets, Vol. 3, pp. 114-116 (1990), which is hereby incorporatedby reference. The enteric coating is applied using conventional particlecoating techniques. If the vegetative cell is granulated with otherexcipients, the resulting granule may also be coated with the entericmaterial.

Diagnosis of IBS in Mammals

The guidelines for IBS diagnosis promulgated under the Rome criteria arefocused upon subjective symptoms, including the continuous or recurrentsymptoms of abdominal pain or discomfort that may be relieved withdefecation, a change in frequency or consistency of stools, and that, atleast 25 percent of the time, the patient experiences altered stoolfrequency (greater than 3 bowel movement per day or less than 3 bowelmovements per week), altered stool form (hard or loose watery stools orpoorly formed stools), passage of mucous stools, or bloating (feeling ofabdominal distention). The present invention provides a method ofdiagnosing irritable bowel syndrome in a patient, based on the patient'smalabsorption of carbohydrates. A patient that has one or more IBSsymptoms (e.g., a symptom classified under the Rome Criteria) isidentified, and a biological sample is obtained from this identifiedpatient. The biological sample can be, e.g., fecal material, urine,blood, serum, plasma, or breath. The amount of a product of agastrointestinal enzyme in the patient-derived sample is thendetermined. For example, the hydrogen gas breath test is used to measurehydrogen gas, which is produced as a result of breakdown of unabsorbedcarbohydrates in the gastrointestinal tract. The amount of the productin the patient-derived sample is compared with a reference amount of aproduct of a gastrointestinal enzyme. This reference amount is obtainedfrom a patient or plurality of patients known not to have IBS or otherdisorders involving carbohydrate malabsorption. An alteration in thetest amount relative to the reference amount indicates that the patienthas irritable bowel syndrome. For example, an increase in hydrogen gasin a patient-derived sample as compared to a reference sample, measuredas described above, indicates poor carbohydrate absorption in thegastrointestinal tract of the patient, leading to the diagnosis of IBS.

Therapeutic Administration

A therapeutic regimen is carried out by identifying a subject, e.g., ahuman patient suffering from (or at risk of developing) IBS andproviding treatment to the subject. For example, patients characterizedas producing less than normal amounts of enzymes that degradecarbohydrates, e.g. lactase or fructase, or other digestive enzymes suchas amylases, lipases or proteases, are diagnosed as suffering from or atrisk of developing IBS, as now described. A composition includingBacillus coagulans bacteria is administered to the patient, such as byoral administration, such that one symptom of IBS is reduced. Inembodiments of the invention, the patient is a female, such as apost-menstrual female, since symptoms of IBS are often more prevalentand/or severe in post-menstrual women. The patient may be apost-menopausal woman. The composition including Bacillus coagulansbacteria is provided prior to or concomitant with the onset of one ormore symptoms of IBS.

Prior to the present invention, dietary management of IBS and otherdiseases associated with carbohydrate malabsorption has focused on thedietary control of a patient's intake of carbohydrate. The inventionprovides a method of dietary management of a subject's carbohydrateabsorption, by identifying a patient having a symptom of carbohydratemalabsorption, and providing Bacillus coagulans bacteria to the subject,which then colonize the subject's gastrointestinal tract, and cause thesubject's carbohydrate absorption to be modulated. Colonization ofBacillus coagulans bacteria in the subject's small and large intestineincreases absorption of dietary carbohydrates including fructose andlactose, therefore reducing pain, abdominal bloating, flatus, diarrhea,constipation, and other symptoms of carbohydrate malabsorption.

The methods allow a clinician to tailor carbohydrate malabsorptiontreatment to more effectively manage patient health and wellness. When apatient presents with one or more symptoms of IBS, the physician is ableto determine the extent of the patient's carbohydrate malabsorption bymeasuring the product of a gastrointestinal enzyme such as fructase orlactase in a sample derived from the patient. Measurement of theenzymatic product is performed by methods known in the art and disclosedherein, including the hydrogen and methane breath tests. The physicianthen provides the compositions described herein in amounts that reduceor eliminate one or more symptoms of IBS.

A therapeutic system for treating, reducing and/or controllingcarbohydrate malabsorption is in the form of a package containing atherapeutic composition containing B. coagulans and a supplementarydigestive enzyme in combination with packaging material. The packagingmaterial includes a label or instructions for use of the components ofthe package. The instructions describe the use of the packaged componentas described herein for the methods or compositions of the invention.

By way of example, and not of limitation, a system can comprise one ormore unit dosages of a composition according to the present invention.Alternatively, the system can alternately contain bulk quantities of acomposition. The label contains instructions for using the therapeuticcomposition in either unit dose or in bulk forms as appropriate, and mayalso include information regarding storage of the composition, diseaseindications, dosages, routes and modes of administration and the likeinformation. Furthermore, depending upon the particular contemplateduse, the system may optionally contain either combined or in separatepackages one or more of the following components: bifidogenicoligosaccharides, flavorings, carriers, and the like components. Oneparticularly preferred embodiment comprises unit dose packages ofBacillus coagulans bacteria, for use in combination with a conventionalliquid product, together with instructions for combining the bacteriawith the liquid product, for use in a therapeutic method.

The methods and compositions described herein are useful in thetreatment of Celiac disease. Celiac disease is a hereditary disorderthat is caused by sensitivity to the gliadin fraction of gluten, acereal protein found in wheat and rye and less so in barley and oats.The prevalence of celiac disease varies from about 1:300 in southwestIreland to about 1:5000 in North America. No single genetic markerexists. Celiac disease may be asymptomatic, but most patients havesteatorrhea that can range from mild to massive. Symptoms are usuallyabsent until food containing gluten has been eaten. The subject thenbegins to pass pale, malodorous, bulky stools, and suffers painfulabdominal bloating. Thus, a diagnosis is made on the basis of thesymptoms and signs, enhanced by laboratory and x-ray studies, andconfirmed by biopsy showing a flat mucosa and by subsequent clinical andhistologic improvement on a gluten-free diet. Also, the 5-g D-xylosetest is usually abnormal, and untreated patients have low C3 and C4,which rise with gluten withdrawal, and normal or increased serum IgA; in33% to 50%, IgM is reduced.

EXAMPLES Example 1 Preparation of Bacillus coagulans

I. Preparation of Vegetative Bacillus coagulans

Bacillus coagulans is aerobic and facultative, and is typically culturedat pH 5.7 to 6.8, in a nutrient broth containing up to 2% (by wt) NaCl,although neither NaCl, nor KCl are required for growth. A pH of about4.0 to about 7.5 is optimum for initiation of sporulation (i.e., theformation of spores). The bacteria are optimally grown at 20° C. to 45°C., and the spores can withstand pasteurization. Additionally, thebacteria exhibit facultative and heterotrophic growth by utilizing anitrate or sulfate source. However, Bacillus coagulans strains and theirgrowth requirements have been described previously (see e.g., Baker, D.et al, 1960. Can. J. Microbiol. 6: 557-563; Nakamura, H. et al, 1988.Int. J. Svst. Bacteriol. 38: 63-73. In addition, various strains ofBacillus coagulans can also be isolated from natural sources (e.g.,heat-treated soil samples) using well-known procedures (see e.g.,Bergey's Manual of Systemic Bacteriology, Vol. 2, p. 1117, Sneath, P. H.A. et al., eds., Williams & Wilkins, Baltimore, Md., 1986).

Bacillus coagulans is cultured in a variety of media, although it hasbeen demonstrated that certain growth conditions are more efficacious atproducing a culture which yields a high level of sporulation. Forexample, sporulation is demonstrated to be enhanced if the culturemedium includes 10 mg/l of MgSO₄ sulfate, yielding a ratio of spores tovegetative cells of approximately 80:20. In addition, certain cultureconditions produce a bacterial spore which contains a spectrum ofmetabolic enzymes particularly suited for the present invention (i.e.,production of lactic acid and enzymes for the enhanced probioticactivity and biodegradation). Although the spores produced by theseaforementioned culture conditions are preferred, various othercompatible culture conditions which produce viable Bacillus coagulansspores may be utilized in the practice of the present invention.

Suitable media for the culture of Bacillus coagulans include: TSB(Tryptic Soy Broth), GYE (Glucose Yeast Extract Broth), and NB (nutrientbroth), which are all well-known within the field and available from avariety of sources. Media supplements which contain enzymatic digests ofpoultry and/or fish tissue, and containing food yeast are particularlypreferred. A preferred supplement produces a media containing at least60% protein, and about 20% complex carbohydrates and 6% lipids. Mediacan be obtained from a variety of commercial sources, notably DIFCO(Newark, N.J.); BBL (Cockeyesville, Md.); and Troy Biologicals (Troy,Md.

II. Preparation of Bacillus coagulans Spores

Dried Bacillus coagulans Hammer bacteria (ATCC No. 31284)spores—prepared as follows. Approximately 1×10⁷ spores were inoculatedinto one liter of culture medium containing: 30 g (wt./vol.) Tryptic SoyBroth; 10 g of an enzymatic-digest of poultry and fish tissue; and 10 gMnSO₄. The culture was maintained for 72 hours under a high oxygenenvironment at 37° C. so as to produce a culture having approximately6×10⁹ cells/gram of culture. The culture was then centrifuged to removethe liquid culture medium and the resulting bacterial paste wasre-suspended in 100 ml of sterile water and 20% malto-dextrin andlyophilized. The lyophilized bacteria were ground to a fine powder byuse of standard good manufacturing practice (GMP) methodologies.

Example 2 Therapeutic Formulations

Formulation #1 Bacillus coagulans (800 Million CFU) Manganese StereateMethyl Cellulose Blue Lake Dye Formulation #2 Bacillus coagulans (800Million CFU) Fructose (3,000 units) Lactose (3,000 units) Lipase (1,500units) Manganese Stereate Methyl Cellulose Formulation #3 Bacilluscoagulans (800 Million CFU) Dibasic Calcium Phosphate Loperamide HCl (2mg) Methyl Cellulose Manganese Stereate Blue Lake Dye Formulation #4Bacillus coagulans (800 Million CFU) Senosides Dibasic Calcium PhosphateLoperamide HCl (2 mg) Methyl Cellulose Manganese Stereate Blue Lake DyeFormulation # 5 Lactase 3,000 FCC units Fructase 2,000 FCC unitsMicro-Crystalline Cellulose Manganese Stearate Blue Lake Dye #1Raspberry Flavor Aspartame Formulation #6 Lactase 3,000 FCC unitsFructase 2,000 FCC units Psylium Husks Micro-Crystalline CelluloseManganese Stearate Blue Lake Dye #1 Formulation #7 Loperamide 2 mgLactase 3,000 FCC units Fructase 2,000 FCC units Micro-CrystallineCellulose Manganese Stearate Blue Lake Dye #1 Formulation #8 SenosidesLactase 3,000 FCC units Fructase 2,000 FCC units Micro-CrystallineCellulose Manganese Stearate Blue Lake Dye #1 Formulation #9 Lysine 125mg Bacillus coagulans (1.5 × 10¹⁰ CFU/g) 53.3 mg Nu Tab 358 mg Mannitol350 mg Red sugar specks 16 mg Magnesium stearate 8 mg Flavor-906.300(Raspberry) 4 mg FD&C Blue #1 Lake 0.2 mg Formulation #10 Bacilluscoagulans (8.0 × 10⁸ CFU) L-lysine cellulose mgnesium Stearatehdroxypropylmethylcellulose mltodextrin favor FD&C blue lake dye redsucrose specks

Other Embodiments

Although particular embodiments have been disclosed herein in detail,this has been done by way of example for purposes of illustration only,and is not intended to be limiting with respect to the scope of theappended claims, which follow. In particular, it is contemplated by theinventors that various substitutions, alterations, and modifications maybe made to the invention without departing from the spirit and scope ofthe invention as defined by the claims. The choice of nucleic acidstarting material, clone of interest, or library type is believed to bea matter of routine for a person of ordinary skill in the art withknowledge of the embodiments described herein. Other aspects,advantages, and modifications considered to be within the scope of thefollowing claims.

1. A method of reducing a symptom of irritable bowel syndrome,comprising identifying a patient suffering from or at risk of developingirritable bowel syndrome, and administering to said patient acomposition comprising Bacillus coagulans bacteria.
 2. The method ofclaim 1, wherein said bacteria is Bacillus coagulans hammer.
 3. Themethod of claim 2, wherein said bacteria is derived from Bacilluscoagulans hammer strain Accession No. ATCC
 31284. 4. The method of claim1, wherein said composition further comprises a supplementary enzyme,wherein said enzyme is selected from the group consisting of a lactase,a fructase, a lipase, an amylase and a protease.
 5. The method of claim1, wherein said symptom is diarrhea or constipation.
 6. The method ofclaim 1, wherein said symptom is alternating diarrhea and constipation.7. The method of claim 1, wherein said symptom is selected from thegroup consisting of gas, bloating and intestinal discomfort.
 8. Themethod of claim 1, wherein said composition further comprises ananti-gas agent.
 9. The method of claim 8, wherein said anti-gas agent isselected from the group of α-galactosidase enzyme, simethicone, calciumcarbonate, aluminum hydroxide and magnesium hydroxide.
 10. The method ofclaim 1, wherein said Bacillus coagulans bacteria are provided at aconcentration of from about 1×10⁸ to about 1×10¹⁰ viable bacteria. 11.The method of claim 1, wherein the Bacillus coagulans bacteria are inthe form of spores.
 12. The method of claim 1, wherein the Bacilluscoagulans bacteria are in the form of vegetative cells.
 13. The methodof claim 1, wherein said composition further comprises an anti-diarrhealagent.
 14. The method of claim 13, wherein said anti-diarrheal agent isselected from the group consisting of loperamide, attapulgite, CrotonLechleri Extract, and calcium polycarbophil.
 15. The method of claim 1,wherein said composition further comprises a laxative agent.
 16. Themethod of claim 15, wherein said laxative agent is selected from thegroup consisting of a senoside, docusate sodium, magnesium hydroxide,and a dietary fiber.
 17. A method of reducing a symptom of irritablebowel syndrome (IBS), comprising identifying a patient suffering from orat risk of developing irritable bowel syndrome, and administering tosaid patient a composition comprising an effective IBS-inhibiting amountof Bacillus coagulans bacteria prior to or concomitant with the onset ofone or more IBS symptoms.
 18. The method of claim 17, wherein saidbacteria is Bacillus coagulans hammer.
 19. The method of claim 18,wherein said bacteria is derived from Bacillus coagulans hammer strainAccession No. ATCC
 31284. 20. The method of claim 17, wherein saidcomposition further comprises a supplementary enzyme, wherein saidenzyme is selected from the group consisting of a lactase, a fructase, alipase, an amylase, and a protease.
 21. The method of claim 17, whereinsaid Bacillus coagulans bacteria are provided at a concentration of fromabout 1×10⁸ to about 1×10¹⁰ viable bacteria.
 22. A method of reducing asymptom of irritable bowel syndrome, comprising identifying a patientsuffering from or at risk of developing irritable bowel syndrome, andadministering to said patient a composition comprising a fructase and alactase.
 23. The method of claim 22, wherein said fructase is providedat a dose of from about 1000 IU to about 12,000 IU, and wherein saidlactase is provided at a dose of from about 1000 IU to about 12,000 IU.24. The method of claim 22, wherein said composition further comprisesan anti-diarrheal agent.
 25. The method of claim 24, wherein saidanti-diarrheal agent is selected from the group consisting ofloperamide, attapulgite, Croton Lechleri Extract, and calciumpolycarbophil.
 26. The method of claim 22, wherein said compositionfurther comprises a laxative agent.
 27. The method of claim 26, whereinsaid laxative agent is selected from the group consisting of a senoside,docusate sodium, magnesium hydroxide, and a dietary fiber.
 28. Themethod of claim 22, wherein said composition further comprises ananti-gas agent.
 29. The method of claim 28, wherein said anti-gas agentis selected from the group of α-galactosidase enzyme, simethicone,calcium carbonate, aluminum hydroxide and magnesium hydroxide.
 30. Amethod of diagnosing irritable bowel syndrome in a patient, comprisingthe steps of: providing a patient-derived biological sample from saididentified patient; determining an amount of a product of agastrointestinal enzyme in said patient-derived sample; and comparingsaid amount in said patient-derived sample with a reference amount of aproduct of a gastrointestinal enzyme, whereby an alteration in the testamount relative to the reference amount indicates that said patient hasirritable bowel syndrome.
 31. The method of claim 30, wherein saidsymptom is selected from the group consisting of diarrhea, constipation,and alternating diarrhea and constipation.
 32. The method of claim 30,wherein said gastrointestinal enzyme is selected from the groupconsisting of a lactase, a fructase, a lipase and a protease.
 33. Amethod of improving stool consistency in a patient afflicted withnon-constipated irritable bowel syndrome, comprising administering aneffective amount of a Bacillus coagulans bacteria, wherein said bacteriaare provided at a concentration of from about 1×10⁸ to about 1×10¹⁰viable bacteria, wherein stool consistency is improved following saidadministration.
 34. A method of decreasing urgency in a subjectafflicted with irritable bowel syndrome, comprising administering aneffective amount of a Bacillus coagulans bacteria, wherein said bacteriaare provided at a concentration of from about 1×10⁸ to about 1×10¹⁰viable bacteria wherein urgency is decreased following saidadministration.
 35. A composition comprising a Bacillus coagulansbacteria, a supplementary lactase, and a supplementary fructase.
 36. Thecomposition of claim 35, wherein said lactase is a β-galactosidase. 37.The composition of claim 35, wherein said lactase is provided in aconcentration from about 1000 IU to about 12,000 IU, and wherein saidfructase is provided in a concentration from about 1000 IU to about12,000 IU.
 38. The composition of claim 35, wherein said lactase isprovided in a concentration of about 3000 IU, and wherein said fructaseis provided in a concentration of about 3000 IU.
 39. The composition ofclaim 35, further comprising one or more components selected from thegroup consisting of an anti-diarrheal agent, an anti-gas agent, alaxative, a vitamin, a mineral, an isolated amino acid, a source ofdietary fiber, and an antibiotic.
 40. The composition of claim 35,further comprising an isolated amino acid.
 41. The composition of claim39, wherein said component is manganese stearate.
 42. The composition ofclaim 39, wherein said source of dietary fiber is selected from thegroup consisting of psyllium husk, soy fiber, citrus fiber, beet fiber,pumpkin seed meal, ground flax, black walnut hull, rice fiber,hydrocollodial polysaccharides, pecan husks, and peanut husks.
 43. Thecomposition of claim 35, further comprising apharmaceutically-acceptable carrier, wherein said carrier comprisessilicone.
 44. The composition of claim 35, wherein said Bacilluscoagulans bacteria is provided at a concentration of from about 1×10⁸ toabout 1×10¹⁰ viable bacteria.
 45. The composition of claim 35, whereinsaid composition is in the form of a capsule, tablet, powder, or liquid.46. The method of claim 35, wherein said Bacillus coagulans bacteria isderived from Bacillus coagulans hammer strain Accession No. ATCC 31284.47. A composition comprising from about 1×10⁸ to about 1×10 ¹⁰ Bacilluscoagulans bacteria, a supplemental lactase provided in a concentrationof about 3000 IU, a supplemental fructase provided in a concentration ofabout 3000 IU, and manganese stearate.
 48. A composition comprising anisolated lactase and an isolated fructase, wherein said isolated lactaseis provided in a concentration from about 1000 IU to about 12,000 IU,and wherein said isolated fructase is provided in a concentration fromabout 1000 IU to about 12,000 IU.
 49. The composition of claim 48,further comprising one or more components selected from the groupconsisting of an anti-diarrheal agent, an anti-gas agent, a laxative, avitamin, a mineral, an isolated amino acid, a source of dietary fiber,and an antibiotic.
 50. The composition of claim 49, wherein saidanti-diarrheal agent is selected from the group consisting ofloperamide, attapulgite, Croton Lechleri Extract, and calciumpolycarbophil.
 51. The composition of claim 49, wherein said laxativeagent is selected from the group consisting of a senoside, docusatesodium, magnesium hydroxide, and a dietary fiber.
 52. The composition ofclaim 49, wherein said anti-gas agent is selected from the group ofsimethicone, calcium carbonate, aluminum hydroxide and magnesiumhydroxide.
 53. A method for increasing carbohydrate absorption in amammal, comprising administering to a mammal a composition comprisingBacillus coagulans bacteria, a supplementary lactase, and asupplementary fructase, wherein carbohydrate absorption is increasedfollowing said administration.
 54. The method of claim 53, wherein saidmammal is diagnosed as suffering from or being at risk of developing adisorder associated with carbohydrate malabsorption.
 55. The method ofclaim 54, wherein said disorder associated with carbohydratemalabsorption is selected from the group consisting of: lactoseintolerance, fructose intolerance, glucose-galactose intolerance,sorbitol intolerance, irritable bowel syndrome, short bowel syndrome,stagnant loop syndrome, celiac disease, chronic malnutrition, chronicpersistent diarrhea, immunoproliferative small intestinal disease,intractable diarrhea of infancy, postenteritis syndrome, tropical sprue,Whipple's disease, Wolman disease, Crohn's disease and ulcerativecolitis.
 56. The method of claim 53, wherein the mammal is human. 57.The method of claim 53, wherein said lactase is provided in aconcentration from about 1000 IU to about 12,000 IU, and wherein saidfructase is provided in a concentration from about 1000 IU to about12,000 IU.
 58. The method of claim 53, wherein said composition furthercomprises one or more components selected from the group consisting ofan anti-diarrheal agent, an anti-gas agent, a laxative, a vitamin, amineral, an isolated amino acid, a source of dietary fiber, and anantibiotic.
 59. A method for increasing lactose digestion, comprisingidentifying a patient suffering from or at risk of developing lactoseintolerance, and administering to said patient a composition comprisingBacillus coagulans bacteria and a supplemental lactase, whereby lactosedigestion is increased following said administration.
 60. The method ofclaim 59, wherein the patient is human.
 61. The method of claim 59,wherein said lactase is provided in a concentration from about 1000 IUto about 12,000 IU.
 62. A composition comprising a Bacillus coagulansbacteria and a supplementary fructase.
 63. The composition of claim 62,wherein said fructase is provided in a concentration from about 1000 IUto about 12,000 IU.
 64. The composition of claim 62, wherein saidfructase is provided in a concentration of about 3000 IU.
 65. Thecomposition of claim 62, further comprising an isolated amino acid. 66.The composition of claim 62, wherein said composition is in the form ofa capsule, tablet, powder, or liquid.
 67. The composition of claim 62,wherein said Bacillus coagulans bacteria are derived from Bacilluscoagulans hammer strain Accession No. ATCC
 31284. 68. A medical food forthe management of irritable bowel syndrome, comprising Bacilluscoagulans bacteria and L-lysine, wherein said medical food is formulatedto provide at least about 1×10⁶ viable Bacillus coagulans bacteria inthe gastrointestinal tract of a mammal per day, based on a serving sizeof about 1 gram to about 2 grams of said medical food taken up to twicea day.
 69. The medical food of claim 68, further comprising asupplemental enzyme selected from the group consisting of a lactase, afructase, a lipase and a protease.
 70. The medical food of claim 68,further comprising one or more components selected from the groupconsisting of an anti-diarrheal agent, an anti-gas agent, a laxative, avitamin, a mineral, an isolated amino acid, a source of dietary fiber,and an antibiotic.
 71. A method of dietary management of a subject'scarbohydrate absorption, comprising the steps of: identifying a patienthaving a symptom of carbohydrate malabsorption; and providing acomposition comprising Bacillus coagulans bacteria to said subject,wherein said bacteria colonize said subject's gastrointestinal tract,whereby carbohydrate absorption by said subject is modulated, such thatthe subject's carbohydrate absorption is managed.
 72. A method ofdietary management of a subject's carbohydrate absorption, comprisingthe steps of: identifying a patient having a symptom of carbohydratemalabsorption; providing a patient-derived biological sample from saididentified patient; determining an amount of a product of agastrointestinal enzyme in said patient-derived sample; comparing saidamount in said patient-derived sample with a reference amount of aproduct of a gastrointestinal enzyme; and providing a compositioncomprising Bacillus coagulans bacteria, whereby the subject'scarbohydrate absorption is managed.
 73. A method for increasingcarbohydrate absorption in a patient diagnosed as suffering from orbeing at risk of developing celiac disease, comprising administering tosaid patient a composition comprising Bacillus coagulans bacteria,wherein carbohydrate absorption in said patient is increased followingsaid administration.
 74. A method of reducing a symptom of irritablebowel syndrome, wherein said symptom comprises alternating diarrhea andconstipation, comprising identifying a patient suffering from or at riskof developing irritable bowel syndrome, and administering to saidpatient a composition comprising Bacillus coagulans bacteria.
 75. Acomposition comprising a Bacillus coagulans bacterium and asupplementary enzyme provided in a formulation with a food product. 76.The composition of claim 75, wherein said food product is a dairyproduct.
 77. A method of reducing flatus, comprising identifying apatient having a symptom of carbohydrate malabsorption, said symptombeing flatus, and administering to said patient a composition comprisingBacillus coagulans bacteria.
 78. The method of claim 77, wherein saidbacteria is Bacillus coagulans hammer.
 79. The method of claim 78,wherein said bacteria is derived from Bacillus coagulans hammer strainAccession No. ATCC
 31284. 80. The method of claim 77, wherein saidcomposition further comprises a supplementary enzyme, wherein saidenzyme is selected from the group consisting of a lactase, a fructase, alipase, an amylase and a protease.
 81. The method of claim 77, whereinsaid composition further comprises an anti-gas agent.
 82. The method ofclaim 81, wherein said anti-gas agent is selected from the group ofα-galactosidase enzyme, simethicone, calcium carbonate, aluminumhydroxide and magnesium hydroxide.